DESCRIPTION: (Applicant's Abstract) Specific and important populations of neurons in the brain are subject to delayed death following short periods of blood flow disruption as occurs in stroke, head trauma, or cardiac arrest. While many neurons are killed outright by the ischemic insult, many populations suffer attrition over a period of several days, retaining many of their normal signaling functions during that time. Some of these populations vulnerable to the delayed death, such as CA1 pyramidal neurons of the hippocampus, are vital parts of learning and memory circuitry of the brain. It is possible that these neurons could be rescued given an understanding of the drawn out death program they undergo. If so, the increasing financial and social costs of rehabilitation and support of survivors of brain injury, an ever-increasing number in an aging population, might be reduced. Many lines of evidence, converge to indicate that severe disruptions in intracellular Ca2+ levels during and shortly after an insult are the immediate trigger for delayed neuronal death, however the drawn out chain of subsequent events, that might be interrupted by suitable interventions, is poorly understood. Our research, using an in vivo model of ischemia has shown that there is a delayed depression of Ca2+ signaling activity in neurons destined to die. This body of data suggests clearly different mechanisms of cell death from currently held views, derived largely from in vitro, culture experiments, that increased Ca2+ burdens on the neurons after insult cause the delayed death. It is proposed here, 1) to investigate further the depression of Ca2+ signaling in post-ischemic CA1 neurons, 2) to investigate whether this depression is responsible for disrupting vital cellular functions that result in delayed death of neurons, and 3) to determine whether certain procedures and drugs that have proven effective in preventing neuronal death are acting by preventing the depression of Ca2+ signaling. If successful this research would suggest new modes of treatment, or give scientific basis for existing experimental treatments, of stroke or trauma that could prove to be effective when begun after significant delay.